Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study.

The Goldie-Coldman model explaining the kinetics of tumor cell kill and drug resistance has a potential application in designing chemotherapy regimes. In this Southwest Oncology Group (SWOG) trial we tested the alternation of two potentially noncrossresistant drug combinations with a concurrent drug combination in patients with limited small-cell lung cancer. The concurrent drug combination consisted of etoposide (VP-16), 75 mg/m2/intravenously (IV), days 1, 2, and 3; vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), 40 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (EVAC). The alternating combination consisted of VP-16, 100 mg/m2/IV, days 1, 2, and 3; and cisplatin (CDDP), 100 mg/m2/IV, day 1, alternating with vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin, 50 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (VP-16/CDDP-VAC). Chemotherapy was administered at 3-week intervals for six cycles both before and after chest (5,000 rads/5 weeks) and whole brain radiotherapy (3,000 rads/2 weeks). One hundred ninety-nine patients received EVAC and 201 received the alternating combination. There was no significant difference in the response rate to the initial six cycles of treatment with EVAC (CR, 40%) versus the alternating combination (CR, 38%). There was no significant difference between the best response, EVAC (CR, 48%) and VP-16/CDDP-VAC (CR, 51%). Median survival for all randomized patients on EVAC is 15.1 months versus 16.5 months on the alternating combination (P = .58). Toxicities consisted primarily of bone marrow suppression, anorexia, nausea and vomiting, peripheral neuropathies, and alopecia. As in previous trials, the chest was the most common site of relapse (33%). There were no differences in the incidence and sites of relapse between the two treatment arms. These treatments appear equally effective at inducing remission and prolonging survival in patients with small-cell lung cancer.

Posttreatment biopsy results following interstitial brachytherapy in early-stage prostate cancer.

PURPOSE: To assess pathologic control rates for prostatic carcinoma as determined by postimplant prostate biopsy in a large series of consecutive patients who have received permanent interstitial brachytherapy using a contemporary transrectal ultrasound-directed, transperineal, computer generated, volume technique. METHODS AND MATERIALS: Four hundred and two patients received permanent 125I or 103Pd interstitial brachytherapy as primary treatment for early stage prostatic carcinoma at the Northwest Tumor Institute between January 1988 and January 1994. Of these, 201 have consented to biopsy 12 or more months postimplant with a median follow-up of 40 months (range: 12-83 months). None had received hormonal manipulation. A total of 361 biopsies was performed on 201 patients with a range of one to six annual biopsies per patient (91 received multiple, serial biopsies). Of the 161 patients more than 12 months postimplant who have not been biopsied, most have been unwilling or unable to submit to biopsy. Only six patients with biochemical progression have not been biopsied. There was no difference in the presenting characteristics or implant parameters between those patients biopsied and those that were not. One hundred and forty-three received 125I (71%) prescribed to a MPD of 160 Gy with a median activity of 35.5 mCi, and 58 (29%) received 103Pd prescribed to a MPD of 115 Gy with a median activity of 123 mCi. Multiple biopsies were performed under transrectal ultrasound guidance, and all specimens were classified as either negative, indeterminate, or positive. RESULTS: At the time of last biopsy, 161 (80%) have achieved negative pathology, 34 (17%) remain indeterminate, and 6 (3%) have been positive. Only 2 of the 186 patients with a PSA < 4.0 ng/ml at the time of biopsy were positive. Among those 33 indeterminate patients with a subsequent biopsy, 28 have converted to negative, 2 to positive, and 3 remain unchanged to date. CONCLUSIONS: These data demonstrate at least an 80% pathologically confirmed local control rate following permanent interstitial brachytherapy for early stage prostate cancer. A higher local control rate is expected with further follow-up as the majority of indeterminate biopsies convert to negative over time. The indeterminate category of postirradiation biopsy described here includes specimens that have probably been interpreted as positive in other series, but correlate clinically and biochemically with negative biopsies. These results support the use of modern interstitial brachytherapy techniques for selected patients with early stage adenocarcinoma of the prostate.

Palladium-103 brachytherapy for prostate carcinoma.

PURPOSE: A report of biochemical outcomes for patients treated with palladium-103 (Pd-103) brachytherapy over a fixed time interval. METHODS AND MATERIALS: Two hundred thirty patients with clinical stage T1-T2 prostate cancer were treated with Pd-103 brachytherapy and followed with prostate-specific antigen (PSA) determinations. Kaplan-Meier estimates of biochemical failure on the basis of two consecutive elevations of PSA were utilized. Multivariate risk groups were constructed. Aggregate PSA response by time interval was assessed. RESULTS: The overall biochemical control rate achieved at 9 years was 83.5%. Failures were local 3.0%; distant 6.1%; PSA progression only 4.3%. Significant risk factors contributing to failure were serum PSA greater than 10 ng/ml and Gleason sum of 7 or greater. Five-year biochemical control for those exhibiting neither risk factor was 94%; one risk factor, 82%; both risk factors, 65%. When all 1354 PSA determinations obtained for this cohort were considered, the patients with a proportion of PSAs < or = 0.5 ng/ml continued to increase until at least 48 months post-therapy. These data conformed to a median PSA half-life of 96.2 days. CONCLUSIONS: Prostate brachytherapy with Pd-103 achieves a high rate of biochemical and clinical control in patients with clinically organ-confined disease. PSA response following brachytherapy with low-dose-rate isotopes is protracted.

10-year biochemical (prostate-specific antigen) control of prostate cancer with (125)I brachytherapy.

PURPOSE: To report 10-year biochemical (prostate-specific antigen [PSA]) outcomes for patients treated with 125I brachytherapy as monotherapy for early-stage prostate cancer. METHODS AND MATERIALS: One hundred and twenty-five consecutively treated patients, with clinical Stage T1-T2b prostate cancer were treated with 125I brachytherapy as monotherapy, and followed with PSA determinations. Kaplan-Meier estimates of PSA progression-free survival (PFS), on the basis of a two consecutive elevations of PSA, were calculated. Aggregate PSA response by time interval was assessed. Comparisons were made to an earlier-treated cohort. RESULTS: The overall PSA PFS rate achieved at 10 years was 87% for low-risk patients (PSA < 10, Gleason Sum 2-6, T1-T2b). Of 59 patients (47%) followed beyond 7 years, 51 (86%) had serum PSAs less than 0.5 ng/mL; 48 (81%) had serum PSAs less than 0.2 ng/mL. Failures were local, 3.0%; distant, 3.0%. No patients have died of prostate carcinoma. The proportion of patients with a PSA < or =0.2 ng/mL continued to increase until at least 7-8 years posttherapy. A plot of PSA PFS against the proportion of patients achieving serum PSA of less than 0.2 ng/mL suggests a convergence of these two endpoints at 10 years. Patients treated in the era of this study (1988-1990) experienced a statistically improved PFS compared with an earlier era (1986-1987). This difference appears independent of patient selection, suggesting that the maturation of the technique resulted in improved biochemical control. CONCLUSION: With modern technique, monotherapy with 125I achieves a high rate (87%) of biochemical and clinical control in patients with low-risk disease at 10 years. The decline of PSA following brachytherapy with low-dose-rate isotopes can be protracted. Absolute PSA and PFS curves merge, and are comparable at 10 years.

Centralized multiinstitutional postimplant analysis for interstitial prostate brachytherapy.

PURPOSE: To investigate the feasibility and utility of performing centralized postimplant analysis for transperineal interstitial permanent prostate brachytherapy (TIPPB) by conducting a pilot study that compares the results obtained from 125I implants conducted at five different institutions. METHODS AND MATERIALS: Dose-volume histogram (DVH) analysis was performed on 10 postimplant CT scans from each of five institutions. This analysis included the total implanted activity of 125I, ultrasound, and CT volumes of the prostate, target-volume ratios, dose homogeneity quantifiers, prostate dose coverage indices, and rectal doses. As a result of the uncertainty associated with the delineation of the prostatic boundaries on a CT scan, the contours were redrawn by a single, study center physician, and a repeat DVH analysis was performed. This provided the basis for comparison between institutions in terms of implant technique and quality. RESULTS: By comparing total activity to preimplant ultrasound volume we clearly demonstrated that differences exist in implant technique among these five institutions. The difficulty associated with determining glandular boundaries on CT scans was apparent, based upon the variability in prostate volumes drawn by the various investigators compared to those drawn by the study center physician. This made no difference, of course, in the TVR or homogeneity quantifiers that are independent of target location. Furthermore, this variability made surprisingly little difference in terms of dose coverage of the prostate gland. Rectal doses varied between institutions according to the various implant techniques. CONCLUSIONS: Centralized, outcome-based evaluation of transperineal interstitial permanent prostate brachytherapy is viable and appropriate. Such an approach could be reasonably used in the conduct of multiinstitutional trials used to study the efficacy of the procedure.

Reduction of radioactive seed embolization to the lung following prostate brachytherapy.

PURPOSE: Ultrasound-guided interstitial implantation of radioactive seeds is a common treatment for early stage prostate cancer. One of the risks associated with this therapy is seed embolization to the lung. This paper reports on the incidence and possible adverse effects of seed migration. METHODS AND MATERIALS: Two hundred ninety consecutive patients were treated with permanent radioactive seed brachytherapy for prostate cancer between January 1 and December 31, 1995. One hundred fifty-four patients were treated with iodine-125 (I-125), and 136 patients were treated with palladium-103 (Pd-103). All but one patient had a routine post implant chest radiograph (CXR), leaving 289 evaluable patients. RESULTS: Twenty radioactive seed pulmonary emboli were identified in 17 patients; 3 patients had two emboli each. The radioactive seed pulmonary embolism rate for the entire group of patients was 5.9%. Acute pulmonary symptoms were not reported by any patient in this series. One hundred forty-six study patients were implanted with free seeds alone (136 Pd-103 and 11 I-125), and 143 were implanted with linked seed embedded in a vicryl suture for the peripheral portions of their implants. The radioactive seed embolization rate by patient was 11% (16/146) versus 0.7% (1/143) for free seed implants and implants utilizing linked seeds, respectively. The difference was statistically significant, p = 0.0002. No patient had detectable morbidity as a consequence of seed emboli. CONCLUSION: The use of linked seeds embedded in vicryl sutures for the peripheral portion of permanent radioactive seed prostate implants significantly reduced the incidence of pulmonary seed embolization in patients treated with the Seattle technique.

Consensus guidelines for high dose rate remote brachytherapy in cervical, endometrial, and endobronchial tumors. Clinical Research Committee, American Endocurietherapy Society.

PURPOSE: A large number of medical centers have recently instituted the use of High Dose-Rate Afterloading Brachytherapy (HDRAB). There is wide variation in treatment regimens, techniques, and dosimetry being used and there are no national standard protocols or guidelines for optimal therapy. METHODS AND MATERIALS: The Clinical Research Committee (CRC) of the American Endocurietherapy Society (AES) met to formulate consensus guidelines for HDRAB in cervical, endometrial, and endobronchial tumors. CONCLUSION: Each center is encouraged to follow a consistent treatment policy in a controlled fashion with complete documentation of treatment parameters and outcome including efficacy and morbidity. Until further clinical data becomes available, the linear quadratic model can be used as a guideline to formulate a new HDR regimen exercising caution when changing from a Low Dose Rate (LDR) to a HDRAB regimen. The treatments should be fractionated as much as practical to minimize long term morbidity. As more clinical data becomes available, the guidelines will mature and be updated by the Clinical Research Committee of the AES.

The role of external beam radiotherapy with I-125/Pd-103 brachytherapy for prostate carcinoma.

BACKGROUND AND PURPOSE: To compare the biochemical outcomes of patients treated with Pd-103/I-125 brachytherapy alone vs. brachytherapy combined with external beam radiotherapy for early stage prostate carcinoma. METHODS: Brachytherapy monotherapy was used in 403 patients. Brachytherapy was combined with 45 Gy of external beam radiotherapy in 231 patients. Median follow-up was 58 months. To compare the biochemical outcomes of these two treatment approaches, patients were stratified into three relative risk groups: low risk, T(1)-T(2), Gleason 2-6/10, PSA< or =10.0; intermediate risk, T(3), Gleason 7-10/10, PSA>10.0 (one factor); high risk, T(3), Gleason 7-10/10, PSA>10.0 (two factors). RESULTS: The actuarial biochemical progression-free rate (bNED) for the entire 634 patients was 85% at 10 years. The bNED outcomes by risk group for monotherapy vs. combined therapy respectively were: low risk, 94 vs. 87%; intermediate risk, 84 vs. 85%; high risk, 54 vs. 62%. These differences did not reach statistical significance for any risk group. Rectal morbidity was slightly greater in the combined treatment patients. CONCLUSION: Although the addition of external beam irradiation to brachytherapy is conceptually appealing for patients with higher risk prostate carcinoma, we were unable to demonstrate a benefit. Whether this is because of patient selection biases within the risk groupings, an artefact of retrospective review, or because external radiotherapy does not offer additional benefit is uncertain.

Does brachytherapy have a role in the treatment of prostate cancer?

The goal of radiation therapy is to deliver a high dose to the tumor while preserving normal surrounding tissue. For early-stage prostate cancer, the ultimate conformal irradiation is to place radioactive sources directly into the gland either as permanent or temporary seeds. Permanent seed implantation is capable of delivering two times the radiobiologically equivalent dose of external beam irradiation to the prostate and tumor. In the past, the results of prostate brachytherapy were likely poor owing to the technical difficulty in accurately placing the radioactive seeds uniformly throughout the prostate. The use of low-dose-rate I-125 to treat high-grade cancers probably also contributed to the poorer results as compared with external beam irradiation. Over the last 10 years, however, technologic advances in transrectal ultrasonography, computer dosimetry, and template-based transperineal techniques have dramatically improved the accuracy and consistency of the brachytherapist to place radioactive sources directly into the prostate gland. Transperineal ultrasound or CT directed seed implantation has replaced the older retropubic method. Brachytherapists are now able to accurately map out the gland prior to the implant and carefully evaluate preoperatively seed placement. The availability of such radioactive sources as iodine-125, palladium-103, and iridium-192 has also given the brachytherapist isotopes that can be more carefully matched to the biology and stage of the tumor. More sensitive definitions of failure have prompted radiation oncologists and urologists to carefully evaluate the efficacy of external beam irradiation and surgery. Accurate comparison of the efficacy of brachytherapy to surgery and to external beam radiation requires a randomized study. Comparisons of retrospective studies are fraught with the problems of the heterogeneous nature of early-stage prostate cancer. Imbalances in stage, grade, initial PSA extraprostatic disease, and nodal status of patient groups make comparisons difficult. Most of the long-term data for permanent seed implantation are the result of work at a single institution. These results will need to be repeated at other institutions treating patients in a similar manner. Because techniques vary from institution to institution, permanent implant results will need to be carefully evaluated for technique as well as stratified for pretreatment variables. Pretreatment PSA and grade appear to be more sensitive variables than stage in predicting failure after radiation. As more patients are diagnosed with very early and nonpalpable disease, future studies will need to stratify patients based on these pretreatment factors. Patients with early-stage disease but identified as high risk for extraprostatic disease will require more intensive regimens. The treatment outcomes based on biopsy results are inconclusive. A lack of consensus on the definition of a truly positive biopsy remains forthcoming. The value of a positive prostate biopsy as an outcome predictor for clinical failure is still unclear. The use of prostate nuclear cell antigen staining may help clarify the issue. Comparison of treatment outcome based on absolute PSA is also difficult. The Seattle series suggest that brachytherapy by permanent seed implantation is as efficacious as external beam irradiation for early-stage disease in patients with a low PSA (< 10 ng/mL). As the PSA value rises above 10 ng/mL, the probability of failure after external beam rises substantially. Results from the Seattle series suggest an advantage to seed implant alone or the judicious application of seed implant boost to external beam radiation for these patients with more advanced cancer. The most sensitive measurement of therapeutic outcome is progression-free survival. Few studies to date have evaluated progression-free survival.

Should brachytherapy be considered a therapeutic option in localized prostate cancer?

Contemporary prostate brachytherapy incorporates advances in computer analysis, imaging technology, and delivery apparatus, allowing exacting and reproducible results compared with historical approaches. The advances permit brachytherapy to be performed on a cost-effective, outpatient basis with low morbidity in the appropriately selected patient. Although unsettled questions remain regarding dosimetric issues, long-term outcomes, and morbidity, the weight of evidence to date appears to support the use of brachytherapy in selected patients. Brachytherapy may be considered a therapeutic option: as monotherapy for early-stage disease and also a boost following moderate doses of external beam irradiation for locally advanced disease.

Permanent prostate seed implant brachytherapy: report of the American Association of Physicists in Medicine Task Group No. 64.

There is now considerable evidence to suggest that technical innovations, 3D image-based planning, template guidance, computerized dosimetry analysis and improved quality assurance practice have converged in synergy in modern prostate brachytherapy, which promise to lead to increased tumor control and decreased toxicity. A substantial part of the medical physicist's contribution to this multi-disciplinary modality has a direct impact on the factors that may singly or jointly determine the treatment outcome. It is therefore of paramount importance for the medical physics community to establish a uniform standard of practice for prostate brachytherapy physics, so that the therapeutic potential of the modality can be maximally and consistently realized in the wider healthcare community. A recent survey in the U.S. for prostate brachytherapy revealed alarming variance in the pattern of practice in physics and dosimetry, particularly in regard to dose calculation, seed assay and time/method of postimplant imaging. Because of the large number of start-up programs at this time, it is essential that the roles and responsibilities of the medical physicist be clearly defined, consistent with the pivotal nature of the clinical physics component in assuring the ultimate success of prostate brachytherapy. It was against this background that the Radiation Therapy Committee of the American Association of Physicists in Medicine formed Task Group No. 64, which was charged (1) to review the current techniques in prostate seed implant brachytherapy, (2) to summarize the present knowledge in treatment planning, dose specification and reporting, (3) to recommend practical guidelines for the clinical medical physicist, and (4) to identify issues for future investigation.

Transperineal ultrasound-guided implantation of the prostate: morbidity and complications.

Two hundred and seventy four patients with early carcinoma of the prostate were treated by ultrasound-guided transperineal I-125 implantation. One hundred and ninety six received implant alone, and 78 were treated with combined external beam and I-125 implantation. Operative, early and late complications were reviewed with a median follow-up time of 40 months (minimum 13, maximum 64 months). Operative complications were negligible. Early morbidity (less than 12 months post implant) was noted in 10-15% of patients and consisted of self-limited irritative uropathy or obstruction. Late complications (more than 12 months post implant) were noted in 13%. Seven percent of patients had some combination of permanent sequelae of treatment: 14 patients had some degree of incontinence, 17 had irritative uropathy symptoms, and 7 had proctitis, 5 of whom resolved spontaneously. Most complications were mild to moderate with a notable absence of severe problems. Urinary morbidity was strongly related to prior or post-implant transurethral resection of the prostate (TURP) (24% with TURP, 3% without). Transperineal implantation in our experience is associated with an acceptable acute and chronic complication rate.

Cystic cerebellar astrocytomas in childhood.

Thirty-nine patients with low grade cystic cerebellar astrocytomas were treated at the University of Washington and Children's Orthopedic Hospital in Seattle, Washington, between 1955 and 1977; 29 were treated with partial or complete resection alone, and 10 received radiation therapy after various types of surgical procedures. With a mean follow-up time of 7 years, the survival rate for patients who had complete resections of their primary disease was 100%. The relapse-free survival rate was 82%. The relapse-free survival rate for patients treated primarily with partial resection alone was 36%. Postoperative irradiation after partial resection for both primary and recurrent disease resulted in a relapse-free survival rate of 83%. If complete tumor excision is not possible, postoperative radiation therapy is recommended following partial resection.

Interstitial implantation techniques in prostate cancer.

Brachytherapy is a radiotherapeutic technique that allows the physician to implant radioactive isotopes into a body cavity or directly into tissue. Different radioisotopes have unique characteristics that the brachytherapist may utilize for a particular situation. The use of brachytherapy is part of standard radiation oncology practice in gynecological and head and neck cancer management. The prostate is approachable for interstitial implantation due to its close proximity to the perineum. Over 20 years ago, primitive methods of brachytherapy were utilized in the treatment of prostate cancer. However, poor results due to inconsistency in achieving adequate coverage of the entire prostate and poor patient selection caused this treatment modality to fall out of favor. Technological advances over the last decade have restored attention to brachytherapy for prostate cancer. Particularly important has been the development of transrectal ultrasound, new radioisotopes such as palladium-103, computer tomography, computerized dosimetry systems, and earlier diagnosis. Modern interstitial implantation utilizing transperineal template and transrectal ultrasound guidance has resulted in improved consistency in radiation dose delivery to the entire prostate. Early results are encouraging in terms of the relatively low morbidity of the procedure, improved local control rates, and biochemical progression free survival. This has resulted in an outpatient treatment that has high patient acceptance.

Brachytherapy for prostate cancer.

Brachytherapy is one of the oldest techniques of radiation therapy for prostate cancer. However, its use has been controversial due to mixed results with older implant techniques and the availability of different treatment methods. New methods of brachytherapy based on improved technology and increased understanding of radiobiology hold promise for consistently improved results. This article describe the various methods of prostate brachytherapy and reviews the clinical results for these methods.

Evaluation of fast neutron teletherapy for advanced carcinomas of the major salivary glands.

This review analyzes the local control rate of fast neutron beam teletherapy for malignant salivary gland carcinomas compared to conventional photon irradiation at the same institution. Thirty patients with malignant parotid or submaxillary gland tumors were treated with either cobalt-60 (19 patients) or neutrons +/- photons (11 patients). The 19 photon-treated patients were historical controls. No advantage is found for neutrons in patients with tumors less than 3 cm where 100% local control was achieved with either modality. In patients with tumor masses 3-6 cm in size, neutrons demonstrated a possible advantage with a local control rate of 100% (followup, 7-18 months) compared to a control rate of 33% with conventional photon irradiation. Acute treatment-related morbidity was slightly greater in neutron-treated patients, but no long-term complications have been observed to date.